The present invention relates to novel bicyclic oxazolidinone compounds and their preparations, more specifically, to R1-substituted bicyclic oxazolidinones as shown in formula I. These compounds have potent activities against gram positive and gram-negative bacteria.
The oxazolidinone antibacterial agents are a novel synthetic class of antimicrobials with potent activity against a number of human and veterinary pathogens, including gram-positive aerobic bacteria such as multiply-resistant staphylococci and streptococci, anaerobic organisms such as bacteroides and clostridia species, and acid-fast organisms such as Mycobacterium tuberculosis and Mycobacterium avium. 
However, oxazolidinones generally do not demostrate an activity at a useful level against aerobic gram-negative organisms. Thus, the use of these oxazolidinone antibacterial agents is limited to infectious states due to gram-positive bacteria. Accordingly, it is among the objects of the present invention to provide pharmaceutical compounds which have broader antibacterial activity including the activity against aerobic gram-negative organisms. We have now discovered that the incorporation of a R1 group at the bicyclic oxazolidinone imparts an unexpected increase in antibacterial activity as well as in the spectrum of activity to include gram-negative organisms such as Haemophilus influenza and Moraxella catarrhalis. More importantly, this increase in the potency and spectrum of activity is only seen in the specified diastereomers of formula I.
U.S. Pat. No. 5,164,510 discloses 5xe2x80x2-indolinyloxazolidin-2-ones of formula XI 
which are useful as antibacterial agents.
U.S. Pat. Nos. 5,036,092; 5,036,093; 5,039,690; 5,032,605 and 4,965,268 disclose aminomethyl oxazolidinyl aza cycloalkylbenzene derivatives useful as antibacterial agents.
U.S. Pat. Nos. 5,792,765 and 5,684,023 disclose substituted oxazolidinones useful as antibacterial agents.
The present invention provides a compound of formula I 
or a pharmaceutically acceptable salt thereof wherein
W is
a) O, or
b) S;
X is
a) xe2x80x94S(xe2x95x90O)mxe2x80x94, or
b) xe2x80x94NR3xe2x80x94;
Y is
a) xe2x80x94Oxe2x80x94,
b) xe2x80x94NHxe2x80x94,
c) xe2x80x94CH2xe2x80x94, or
d) xe2x80x94S(xe2x95x90O)mxe2x80x94;
R1 is C1-4 alkyl, optionally substituted with 1-3 R5;
R2 is
a) H,
b) C1-6 alkyl, optionally substituted with 1-3 halo;
c) cyclopropyl,
d) xe2x80x94OC1-4 alkyl,
e) xe2x80x94NH2,
f) xe2x80x94NHC1-6 alkyl, or
g) xe2x80x94N(C1-6 alkyl)2;
R3 is
a) C1-8 alkyl, optionally substituted with 1-3 halo, CN, NO2, OH, SH or NH2,
b) xe2x80x94C(xe2x95x90O)R4, or
c) xe2x80x94C(xe2x95x90S)NHC1-4 alkyl;
R4is
a) H,
b) C1-6 alkyl, optionally substituted with OH, C1-4 alkoxy, NH2, SH or halo, or
c) xe2x80x94CH2OC(xe2x95x90O)C1-4 alkyl;
R5is
a) halo,
b) xe2x80x94CN,
c) xe2x80x94OH,
d) xe2x80x94SH,
e) xe2x80x94NH2,
f) xe2x80x94OR6,
g) xe2x80x94NHR6,
h) xe2x80x94N(R6)2, or
i) xe2x80x94S(xe2x95x90O)mR6;
R6 is
a) C1-6 alkyl,
b) xe2x80x94C(xe2x95x90O)C1-4 alkyl,
c) xe2x80x94C(xe2x95x90O)OC1-4 alkyl,
d) xe2x80x94C(xe2x95x90O)NH2,
e) xe2x80x94C(xe2x95x90O)NHC1-4 alkyl, or
f) xe2x80x94SO2C1-4 alkyl;
m is 0, 1 or 2;
n is 0 or 1;
with the proviso that where n is 0, Y is xe2x80x94CH2xe2x80x94.
In another aspect, the present invention also provides:
a pharmaceutical composition comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient (the composition preferably comprises a therapeutically effective amount of the compound or salt),
a method for treating gram-positive microbial infections in humans or other warm-blooded animals by administering to the subject in need a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof,
a method for treating gram-negative microbial infections in humans or other warm-blooded animals by administering to the subject in need a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof.
The invention also provides some novel intermediates and processes disclosed herein that are useful for preparing compounds of formula I.
The following definitions are used, unless otherwise described.
The term halo refers to fluoro, chloro, bromo, or iodo.
The term alkyl, alkoxy, etc. refer to both straight and branched groups, but reference to an individual radical such as xe2x80x9cpropylxe2x80x9d embraces only the straight chain radical, a branched chain isomer such as xe2x80x9cisopropylxe2x80x9d being specifically referred to.
The carbon atom content of various hydrocarbon-containing moieties is indicated by a prefix designating the minimum and maximum number of carbon atoms in the moiety, i.e., the prefix Ci-j indicates a moiety of the integer xe2x80x9cixe2x80x9d to the integer xe2x80x9cjxe2x80x9d carbon atoms, inclusive. Thus, for example, C1-7 alkyl refers to alkyl of one to seven carbon atoms, inclusive.
The compounds of the present invention are generally named according to the IUPAC or CAS nomenclature system. Abbreviations which are well known to one of ordinary skill in the art may be used (e.g. xe2x80x9cPhxe2x80x9d for phenyl, xe2x80x9cMexe2x80x9d for methyl, xe2x80x9cEtxe2x80x9d for ethyl, xe2x80x9chxe2x80x9d for hour or hours and xe2x80x9crtxe2x80x9d for room temperature).
It will be appreciated by those skilled in the art that compounds of the present may have additional chiral centers and be isolated in optically active or racemic form. The present invention encompasses any racemic, optically-active (such as enantiomers, diastereomers), tautomeric, or stereoisomeric form, or mixture thereof, of a compound of the invention.
Specific and preferred values listed below for radicals, substituents, and ranges, are for illustration only; they do not exclude other defined values or other values within defined ranges for the radicals and substituents.
Specifically, C1-4 alkyl, C1-6 alkyl and C1-8 alkyl can be an alkyl group having one to four, one to six, or one to eight carbon atoms respectively such as, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl and their isomeric forms thereof; C1-4 alkoxy can be an alkyl group having one to four carbon atoms attached to an oxygen atom of hydroxyl group such as, for example, methoxy, ethoxy, propyloxy, butyloxy and their isomeric forms thereof.
A preferred value for halo is fluoro or chloro.
A preferred value for W is sulfur atom.
A preferred value for X is xe2x80x94NR3xe2x80x94 wherein R3 is as defined above.
A preferred value for Y is xe2x80x94CH2xe2x80x94 or oxygen atom.
A preferred value for R1 is methyl or methyl substituted with fluoro.
A more preferred value for R1 is methyl.
A specific value for R2is C1-6 alkyl, C1-6 alkyl substituted with 1-3 halo, NH2, NHC1-6 alkyl, or N(C1-6 alkyl)2;
A preferred value for R2 is methyl, ethyl, dichloromethyl, dichloroethyl, or NH2.
A more preferred value for R2 is methyl and ethyl.
A specific value for R3 is C1-8 alkyl, C1-8 alkyl substituted with 1-3 halo, CN, NO2, OH, SH or NH2, C(xe2x95x90S)NHC1-4 alkyl, or C(xe2x95x90O)R4 wherein specific value for R4 is H, C1-6 alkyl, optionally substituted with OH, C1-4 alkoxy, NH2, SH or halo, or CH2 OC(xe2x95x90O)C1-4 alkyl.
A preferred value for R3 is 2-fluoroethyl, glycolyl, formyl, methoxyacetyl, oxoethylacetate, acetyl, or methylaminocarbothioyl.
A more preferred value for R3 is formyl or acetyl.
A specific value for R5 is halo, xe2x80x94CN, xe2x80x94OH, xe2x80x94SH, xe2x80x94NH2, xe2x80x94OR6, xe2x80x94NHR6, xe2x80x94N(R6)2, or xe2x80x94S(xe2x95x90O)R6.
A specific value for R6 is C1-6 alkyl, xe2x80x94C(xe2x95x90O)C1-4 alkyl, xe2x80x94C(xe2x95x90O)OC1-4 alkyl, xe2x80x94C(xe2x95x90O)NH2, xe2x80x94C(xe2x95x90O)NHC1-4 alkyl, or xe2x80x94SO2C1-4 alkyl.
Examples of the present invention are:
a) N-({(5S)-3-[(2R)-1-(2-fluoroethyl)-2-methyl-2,3-dihydro-1H-indol-5-yl]-2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide;
b) N-{[(5S)-3-((2R)-1-glycoloyl-2-methyl-2,3-dihydro-1H-indol-5-yl)-2-oxo-1,3-oxazolidin-5-yl]methyl}acetamide;
c) N-({(5S)-3-[(2R)-1-glycoloyl-2-methyl-2,3-dihydro-1H-indol-5-yl]-2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide;
d) N-({(5S)-3-[(2R)-1-formyl-2-methyl-2,3-dihydro-1H-indol-5-yl]-2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide;
e) N-({(5S)-3-[(2R)-1-formyl-2-methyl-2,3-dihydro-1H-indol-5-yl]-2-oxo-1,3-oxazolidin-5-yl}methyl)propanamide;
f) N-({(5S)-3-[(2R)-1-formyl-2-methyl-2,3-dihydro-1H-indol-5-yl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide;
g) N-({(5S)-3-[(2R)-1-(2-methoxyacetyl)-2-methyl-2,3-dihydro-1H-indol-5-yl]-2oxo-1,3-oxazolidin-5-yl}methyl)acetamide;
h) 2-((2R)-5-{(5S)-5-[(acetylamino)methyl]-2-oxo-1,3-oxazolidin-3-yl}-2-methyl-2,3-dihydro-1H-indol-1-yl)-2-oxoethyl acetate;
i) N-({(5S)-3-[(2R)-1-acetyl-2-methyl-2,3-dihydro-1H-indol-5-yl]-2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide;
j) N-[((5S)-3-{(2R)-2-methyl-1-[(methylamino)carbothioyl]-2,3-dihydro-1H-indol-5-yl}-2-oxo-1,3-oxazolidin-5-yl)methyl]acetamide;
k) 2-((2R)-5-{(5S)-5-[(ethanethioylamino)methyl]-2-oxo-1,3-oxazolidin-3-yl}-2-methyl-2,3-dihydro-1H-indol-1-yl)-2-oxoethyl acetate;
l) N-({(5S)-3-[(2R)-1-glycoloyl-2-methyl-2,3-dihydro-1H-indol-5-yl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide;
m) N-{[(5S)-3-[(2R)-1-formyl-2-methyl-1,2,3,4-tetrahydro-6-quinolinyl]-2-oxo-1,3-oxazolidin-5-yl]methyl}acetamide;
n) N-{[(5S)-3-[(2R)-1-glycoloyl-2-methyl-1,2,3,4-tetrahydro-6-quinolinyl]-2-oxo-1,3-oxazolidin-5-yl]methyl}acetamide;
o) N-({(5S)-3-[(2R)-1-formyl-2-methyl-1,2,3,4-tetrahydro-6-quinolinyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide;
p) N-({(5S)-3-[(2R)-1-formyl-2-methyl-1,2,3,4-tetrahydro-6-quinolinyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide;
q) N-{[(5S)-3-[(3R)4-Formyl-3-methyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl]-2-oxo-1,3-oxazolidin-5-yl]methyl}acetamide;
r) N-({(5S)-3-[(3R)-4-Formyl-3-methyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl]-1,2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide;
s) N-({(5S)-3[(3R)-4-Formyl-3-methyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide;
t) N-({(5S)-3-[(2R)2-(fluoromethyl)-1-formyl-2,3-dihydro-1H-indol-5-yl]-2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide;
u) N-{[(5R)-3-(2(+)-methyl-2,3-dihydro-1-benzothien-5-yl)-2-oxo-1,3-oxazolidin-5-yl]methyl}acetamide; or
v) N-[[(5S)-3-[2-(1,1-dimethylethyl)-1-formyl-2,3-dihydro-1H-indol-5-yl]-2-oxo-5-oxazolidinyl]methyl]ethanethioamide.
Preferred examples of the present invention are:
a) N-({(5S)-3-[(2R)-1-formyl-2-methyl-2,3-dihydro-1H-indol-5-yl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide;
b) N-({(5S)-3-[(2R)-1-(2-methoxyacetyl)-2-methyl-2,3-dihydro-1H-indol-5-yl]-2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide;
c) 2-((2R)-5-{(5S)-5-[(acetylamino)methyl]-2-oxo-1,3-oxazolidin-3-yl}-2-methyl-2,3-dihydro-1H-indol-1-yl)-2-oxoethyl acetate;
d) N-({(5S)-3-[(2R)-1-acetyl-2-methyl-2,3-dihydro-1H-indol-5-yl]-2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide;
e) N-[((5S)-3-{(2R)-2-methyl-1-[(methylamino)carbothioyl]-2,3-dihydro-1H-indol-5-yl}-2-oxo-1,3-oxazolidin-5-yl)methyl]acetamide;
f) 2-((2R)-5-{(5S)-5-[(ethanethioylamino)methyl]-2-oxo-1,3-oxazolidin-3-yl}-2-methyl-2,3-dihydro-1H-indol-1-yl)-2-oxoethyl acetate;
g) N-({(5S)-3-[(2R)-1-glycoloyl-2-methyl-2,3-dihydro-1H-indol-5-yl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide;
h) N-({(5S)-3-[(2R)-1-formyl-2-methyl-1,2,3,4-tetrahydro-6-quinolinyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide;
i) N-({(5S)-3-[(2R)-1-formyl-2-methyl-1,2,3,4-tetrahydro-6-quinolinyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide;
j) N-({(5S)-3-[(3R)4-Formyl-3-methyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl]-2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide;
k) N-({(5S)-3-[(3R)-4-Formyl-3-methyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide; or
l) N-[[(5S)-3-[2-(1,1-dimethylethyl)-1-formyl-2,3-dihydro-1H-indol-5-yl]-2-oxo-5-oxazolidinyl]methyl]ethanethioamide.
More preferred examples of the present invention are:
a) N-({(5S)-3-[(2R)-1-formyl-2-methyl-2,3-dihydro-1H-indol-5-yl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide;
b) N-({(5S)-3-[(2R)-1-glycoloyl-2-methyl-2,3-dihydro-1H-indol-5-yl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide;
c) N-({(5S)-3-[(2R)-1-formyl-2-methyl-1,2,3,4-tetrahydro-6-quinolinyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide; or
d) N-({(5S)-3-[(3R)-4-Formyl-3-methyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide.
The following Schemes describe the preparation of compounds of the present invention. All of the starting materials are prepared by procedures described in these schemes or by procedures that would be well known to one of ordinary skill in organic chemistry. The variables used in the Schemes are as defined below or as in the claims. The compounds of this invention can be prepared in accordance to one or more of the processes discussed below.
Indolines
As shown in Chart I, 2-alkylindolines can be prepared from known compound indole 1. Boc-protection of the indole nitrogen using di-t-butyldicarbonate and catalytic DMAP followed by regioselective metalation with n-butyllithium, sec-butyllithium or tert-butyllithium and alkylation with an appropriate electrophile such as alkyl bromides and iodides gives N-Boc-2-alkylindoles 3 (R is an alkyl or a electrophile group). Removal of the boc-protecting group affords 2-alkylindoles 4 which can be nitrated with NaNO3 in sulfuric acid to give 2-alkyl-5-nitroindoles 5. Structure 5 is then reacted with sodium cyanoborohydride to give reduction product, the racemic indolines 6. The nitro group can then be reduced by catalytic hydrogenation in the presence of a suitable catalyst, such as palladium on carbon in a suitable solvent such as ethylacetate, THF, methanol or combinations thereof to afford the 2-alkyl-5-aminoindolines 7 as racemic mixtures. Treatment of 7 with benzyl chloroformate (2 equivalents) in THF with an appropriate base, such as sodium bicarbonate, potassium carbonate or triethylamine gives the bis-Cbz-protected materials of general structure 8. Alternatively, the intermediate R,S-2-alkylnitroindolines can be separated via chiral HPLC to afford enentiomerically pure R- and S-2-alkyl-5-nitroindolines 9 and 10. These materials can then be taken on separately in a chiral synthesis of the desired analogs.
In addition, where other groups besides alkyl are desired at the 2-position of the indoline, one can start with the known ethyl 5-nitroindole-2-carboxylate 11 (Chart II). Reduction of the nitro group to ethyl 5-aminoindole-2-carboxylate can be done via hydrogenation. Structure 12 then be reduced to the indoline intermediate 13 according to the procedure of Young et.al. (Tetrahedron Lett. 1986, 27, 2409-2410) with magnesium in methanol. Bis-protection of the nitrogens with the Cbz-group using benzyl chloroformate provides 14. Reduction of the ester to the alcohol 15 with an appropriate base such as LAH, NaBH4 or DIBAL in a solvent such as diethyl ether or THF or methanol can then be done. Protection of the hydroxyl group with an appropriate protecting group (Rxe2x80x2) such as a silyl or benzyl ether provides 16.
The protected indolines thus prepared can be converted to the final oxazolidinone analogs as outlined in Chart III (R is H, an alkyl group or ORxe2x80x2; wherein Rxe2x80x2 is a protecting group). The carbamate derivatives 8, 16 and 18 can be deprotonated with a lithium base such as n-butyllithium, lithium diisopropylamide (LDA), or lithium bis(trimethylsilyl)amide (LHMDS) in a suitable solvent such as THF, N,N-dimethylformamide (DMF), or mixtures thereof, at a suitable temperature, typically in a range from xe2x88x9278xc2x0 C. to xe2x88x9240xc2x0 C. to give a lithiated intermediate which is directly treated with R-(xe2x88x92)-glycidyl butyrate. Warming to room temperature then affords (hydroxymethyl)oxazolidinones 19. In cases where racemic starting materials are used, compound 19 is obtained as a mixture of two diastereoisomers. In the event that enantiomerically pure intermediates are employed, compound 19 is obtained as one diastereomer. The diastereomeric mixtures of (hydroxymethyl)oxazolidinones 19 can be separated via chiral HPLC into single compounds and crystallized in an appropriate solvent such as CHCl3, Et2O, CH2Cl2, hexane, alcohol, ethyl acetate, THF, acetone or a mixture of them thereof to obtain x-ray structures to determine the absolute stereochemistry.
As shown in Chart III, the hydroxymethyl derivatives can be converted to the corresponding mesylate 20 (Rxe2x80x2=Me) or nosylate 20 (Rxe2x80x2=3-NO2Ph) by treatment with methanesulfonyl chloride in the presence of triethylamine or pyridine, or meta-nitrophenylsulfonyl chloride in the presence of pyridine respectively. The resulting sulfonate 20 can be treated with an alkali metal azide, such as potassium or sodium azide in an aprotic solvent such as DMF, or N-methylpyrrolidinone (NMP) with an optional catalyst such as 18-crown-6 at a temperature in the range of 50-90xc2x0 C. to afford azides 21. The azides can be reduced to the corresponding amine 22 by hyrdrogenation in the presence of a palladium, platinum or nickel catalyst, in an appropriate solvent such as THF, ethyl acetate, or methanol. Alternatively, azides 21 can be reduced to amines 22 by treatment with triphenylphosphine or other trivalent phosphorous compounds in a solvent such as THF, followed by addition of water and heating to temperatures up to 65xc2x0 C. A more direct route to the amines 22 is to reflux the sulfonates 20 in isopropanol/THF/ammonium hydroxide under a dry ice/acetone condenser. The amines 22 thus obtained can be acylated by reactions well known to those skilled in the art to give (acylaminomethyl)oxazolidinones of structural formula 23. It can also be seen that other acyl derivatives, such as carbamates, can be prepared under similar conditions. Furthermore, treatment of intermediates 23 (Wxe2x95x90O) with Lawesson""s reagent in refluxing toluene or THF will afford thioamides 23 (Wxe2x95x90S). The Cbz-group of the (acylaminomethyl)oxazolidinones 23 can be removed via hydrogenation in the presence of an appropriate catalyst such as palladium on carbon in solvents such as THF, methanol, ethyl acetate, dichloromethane or mixtures thereof to afford deprotected intermediates of general structure 24. Alternatively, solvolysis of Cbz-derivatives 23 in 40% HBr/acetic acid followed by removal of solvent provides deprotected intermediates 24 as hydrobromide salts. The deprotected materials can be acylated by reactions well known to those skilled in the art to give oxazolidinones of structural formula 25 (R3=acyl). It can also be seen that other acyl derivatives, such as carbamates, can be prepared under similar conditions. In addition, the deprotected materials can be alkylated by reactions well known to those skilled in the ad to give oxazolidinones of structural formula 25 (R3=alkyl).
Where other substitution on the 2-position of the indoline is desired, the protected alcohol derivatives 25 (R=OSiR3, or OBn) can be deprotected with flouride in the case of the silyl ethers or catalytic hydrogenation in the case of the benzyl ethers. The resulting alcohols 26 can be alkylated to prepare other ether derivatives 27 (Rxe2x80x2xe2x80x3=O-alkyl) or acylated to give esters 27 (Rxe2x80x2xe2x80x3=O-acyl). Alternatively, they can be activated as sulfonates and displaced with nucleophiles to yield aminomethyl derivatives 27 (Rxe2x80x2xe2x80x3=NH2 or NHalkyl) which can be acylated, sulfonylated and/or alkylated to give 27 (Rxe2x80x2xe2x80x3=NHCOH, NHCOalkyl, NHSO2alkyl) by methods well known to those trained in the art. Finally, such alcohols may be converted to the fluoro derivative via treatment with (diethylamino)sulfur trifluoride.
Benzthiophenes
Chart IV (R1is as defined above and Rxe2x80x2 is a protecting group) shows the synthesis of 2-substituted-2,3-dihydro-1-benzothiophene intermediates 33 and 39. Aniline 29 can be prepared by reacting a known compound, methyl 5-nitro-1-benzothiophene-2-carboxylate 28 (Syn. Comm. 1991, 21, 959-964), with Raney nickel or stannous chloride in refluxing ethanol. Cbz-protection and reduction to the benzothiophene 31 can be obtained according to the method descried in Youn et.al. (Tetrahedron Lett. 1986, 27, 2409-2410) using magnesium in methanol. Following the procedure described in Chart II, ester 31 can be converted to the protected alcohol 33. If desired, the sulfur atom can be oxidized to the sulfoxide or sulfone at various stages in the synthesis by methods well known to those skilled in the art.
Alternatively, the requisite 2-substituted benzothiophenes can be prepared via thio-Claisen rearrangement of allyl aryl sulfoxides 37 (J.C.S. Chem. Comm. 1974, 850). The requisite allylic sulfides 36 can be prepared from a commercially available compound, 4-aminothiophenol, to give structure 35, via the protection of the aniline with benzyl chloroformate. The allylation of the sulfide with allylic halides provides 36 which can be oxidized to the sulfoxides 37 with a sodium periodate. Thermal rearrangement in an appropriate solvent such as dimethylaniline or DMF at temperatures ranging from 100-150xc2x0 C. provides the desired intermediates 38. The sulfoxide can be mantained throughout the synthesis or it can be reduced to the sulfides 39 at this time via various methods such as using NaI and trifluoroacetic anhydride in acetone (J. Org. Chem 1994, 58, 3459-3466); or BF3.OEt2 and NaI in acetonitrile (Tetrahedron Asymmetry 1997, 8, 3503-3511); or triphenylphosphine and catalytic ReOCl3(PPh3)2 in dichloromethane (Tetrahedron Lett. 1996, 7941-7944). The remaining steps which lead 33 and 39 to the desired oxazolidinone analogs of type 40a and 40b are similar to these described in Charts I-IV.
Dihydrobenzofurans
As shown in Chart V (wherein R is an alkyl group, Rxe2x80x2 is a protecting group, and R1 is as defined above), 2,3-dihydrobenzofuran analogs of type 48 can be prepared from a known compound, methyl 5-nitro-2,3-dihydro-2-benzofurancarboxylate 41 (Cham. Pharm. Bull. 1989, 37, 2361-2368). The nitro group of structure 41 can be converted to the Cbz-protected aniline 42 by using the method described above for the indoline analogs. Reduction of the ester to the alcohol also as described above provides 43. This material can be protected as an appropriate ether derivative 44, or deoxygenated to the methyl intermediate 45 or oxidized to the aldehyde 46 via a Swern oxidation. Olefination of the aldehyde provides intermediates of type 47 which can be reduced via catalytic hydrogenation later in the synthesis. The remaining steps which lead 44, 45, 47 to the desired oxazolidinone analogs of type 48 are similar to these described in Charts I-IV.
Tetrahydroquinolines
Chart VI illustrates the synthesis of requisite 6-amino-2-alkyl-ttetrahydroquinolines analogs 58. Structure 51 can be prepared through the reduction of a known compound, methyl 6-nitro-2-quinolinecarboxylate 49, to the corresponding alcohol 50 followed by the protection of the alcohol group with an appropriate protecting group such as a silyl ether. The alcohol can also be converted to the aldehyde 52 via Swern oxidation. Olefination of the aldehyde provides alkenes of type 53. Structure 53 can be reduced to the aminoquinolines 54 with stannous chloride. Hydrogenation of materials 54 in the presence of platinum oxide provides the requisite 6-amino-2-alkyl-tetrahydroquinolines 55 as racemic mixtures. In the case of the 2-methyl derivative, the synthesis may be shortened by starting with commercially available 6-nitro-2-methylquinoline 56. The remaining steps that lead structure 57 to the final oxazolidinone analogs 58 are similar to the methods described in Chart I-V.
Benzoxazines and Benzothiazines
Chart VII depicts the preparation of the 7-amino-3-alkyl-3,4-dihydro-2H-1,4-benzoxazines and 7-amino-3-methyl-3,4-dihydro-2H-1,4-benzothiazins. Starting from structure 59, 7-amino-3-methyl-3,4-dihydro-2H-1,4-benzothiazins, 2,5-dinotrophenol, the formation of the triflate 60 followed by displacement with methylthiolate provides 61. Reduction of the nitro groups with Raney nickel or stannous chloride affords the bisaniline 62 (Yxe2x95x90S), which can be converted to the bis-phthalimid 63 (Yxe2x95x90S) with BBr3 in a suitable solvent such as in CH2Cl2. Removal of the methyl group according to the procedure of Young et al (Tetrahedron Lett. 1984, 25, 1753-1756) affords the thiophenol 64 (Yxe2x95x90S). Alternatively, treatment of 2,5-diaminoanisole 62 (Xxe2x95x90O) with excess phthalic anhydride affords the bis-phthalimide 63 (Yxe2x95x90O). Structure 63 then can be converted to the phenol 64 (Yxe2x95x90O) with BBr3 in a suitable solvent such as CH2Cl2.
Oxe2x80x94 or S-alkylation of the phenol derivatives 64 with an appropriate xcex1-chloroketone (R=alkyl) or methyl chloropyruvate (R=CO2Me) in the presence of potassium iodide and a suitable base, such as potassium carbonate provides intermediates of type 65. Bis-deprotection of the amino groups with hydrazine is accompanied by cyclization to the imines 66 (R=alkyl, CO2CH3). Reduction of the imines with sodium borohydride or sodium cyanoborohydride will afford the desired 7-amino-3-substituted-3,4-dihydro-2H-1,4-benzoxazines 67 (Yxe2x95x90O) and 7-amino-3-substituted-3,4-dihydro-2H-1,4-benzothiazins 67 (Yxe2x95x90S) as racemic mixtures 67 (R=alkyl or CO2Me). These compounds can be bis-protected with Cbz-chloride to give intermediates 68. The ester side chain can be manipulated as described above to allow the preparation of other variously substituted analogs. The remaining steps that lead structure 68 to the final oxazolidinone analogs 69 are similar to the methods described in Chart I-V.
Another method for the preparation of benzothiophenes is illustrated in Chart XI. Chart XI shows the synthesis of 2-substituted-2,3-dihydro-1-benzothiophene analogs. Beginning with commercially available 2-chloro-5-nitro-benzaldehyde 104 condensation with methyl thioglycolate and subsequent decarboxylation gives 105 (J. Amer. Chem. Soc. 1948, 70, 1955-1958). Oxidation to the sulfone 106, followed by hydrogenation and protection of the resulting amine with the 2,5-dimethylpyrrole group (Synthesis, 1998, 1599-1603) gives 107. Regioselective metalation with n-butyllithium or lithium bis(trimethylsilyl)amide and alkylation with an appropriate electrophile gives 108. Reduction of the sulfone with lithium aluminum hydride followed by removal of the protecting group and Cbz-protection gives 110. The sulfone in 108 can be maintained in the protecting group manipulation to give the intermediate 113. The remaining steps which lead 110 and 113 to the desired oxazolidinone analogs of type 111, 112, and 114 are similar to those described in Charts I-IV.
Tetrahydroquinoxalines
Chart VIII illustrates the preparation of the 2-alkyl-1,2,3,4-tetrahydro-6-quinoxalinylamine analogs. Condensation of the commercially available 1-chloro-2,4-dinitrobenzene 75 with an appropriately protected amino alcohol derivative 72 provides intermediates of structure 76. The aniline nitrogen of intermediates 76 can be protected with the Boc-group to give 77. Removal of the O-protecting group followed by mesylation provides 78. Treatment of mesylates with hydrogen in the presence of an appropriate catalyst at high dilution results in simultaneous reduction of the nitro-groups and ring closure to yield the desired 2-alkyl-1,2,3,4tetrahydro-6-quinoxalinylamines 79. The remaining steps that lead structure 79 to the final oxazolidinone analogs 82 are similar to the methods described in Chart I-V.
Chart IX illustrates the preparation of 3-substituted-2,3-dihydro-1,4-benzoxathiine analogs from a known know compound 83, 2-(benzyloxy)-4-nitrobenzenethiol (J. Am. Chem. Soc. 1950, 72, 3420). Simultaneous reduction of the nitro group and removal of the benzyl moiety via catalytic hydrogenation in the presence of an appropriate catalyst and treatment with benzylchloroformate provides the protected aniline 84. The treatment of this material with ethyl xcex1-bromoacrylate 85 according to the method described in Martin et.al. (J. Org. Chem. 1974, 39, 1811-1814) provides the 1,4-benzoxathian intermediate 86. The ester can be reduced to the alcohol 87, then converted to the olefins 89 or protected as an ether 90, or deoxygenated to give 91. The remaining steps that lead structure 89, 90 and 91 to the final oxazolidinone analogs 92 are similar to the methods described in Chart I-V.
If desirable, the sulfur atom can be oxidized to the sulfoxide or sulfone at various stages in the synthesis by well-known methods.
Chart X depicts the synthesis of 2-substituted-3,4-dihydro-2H-1,4-benzothiazine analogs. The treatment of a commercially available compound 93 with methanethiol provides compound 94. Demethylation of the sulfur according to the method of Young (Tetrahedron Lett. 1984, 25, 1753-1756) followed by reduction of the nitro groups with stannous chloride in refluxing ethanol provides the diaminothiophenol 95. The treatment of 95 with ethyl xcex1-bromoacrylate 85 according to the method of described in Martin et.al. (J. Org. Chem. 1974, 39, 1811-1814) provides 1,4-benzothiazine intermediate 96. Biz-protection with 2 equivalents of benzyl chloroformate provides compound 97. The ester 97 can be converted to the desired analogs 103 via methods already described above.
These compounds are useful for the treatment of microbial infections, including ophthalmologic infections, in humans and other warm blooded animals, under both parental and oral administration.
The pharmaceutical compositions of this invention may be prepared by combining the compounds of Formula I of this invention with a solid or liquid pharmaceutically acceptable carrier and, optionally, with pharmaceutically acceptable adjuvants and excipient employing standard and conventional techniques. Solid form compositions include powders, tablets, dispersible granules, capsules, cachets and suppositories. A solid carrier can be at least one substance which may also function as a diluent, flavoring agent, solubilizer, lubricant, suspending agent, binder, tablet disintegrating agent, and encapsulating agent. Inert solid carriers include magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, cellulosic materials, low melting wax, cocoa butter, and the like. Liquid form compositions include solutions, suspensions and emulsions. For example, there may be provided solutions of the compounds of this invention dissolved in water and water-propylene glycol and water-polyethylene glycol systems, optionally containing suitable conventional coloring agents, flavoring agents, stabilizers and thickening agents.
Preferably, the pharmaceutical composition is provided employing conventional techniques in unit dosage form containing effective or appropriate amounts of the active component, that is, the compounds of formula I according to this invention.
The quantity of active component, that is the compound of formula I according to this invention, in the pharmaceutical composition and unit dosage form thereof may be varied or adjusted widely depending upon the particular application, the potency of the particular compound and the desired concentration. Generally, the quantity of active component will range between 0.5% to 90% by weight of the composition.
In therapeutic use for treating, or combating, bacterial infections in warm-blooded animals, the compounds or pharmaceutical compositions thereof will be administered orally, topically, transdermally, and/or parenterally at a dosage to obtain and maintain a concentration, that is, an amount, or blood-level of active component in the animal undergoing treatment which will be antibacterially effective. Generally, such antibacterially effective amount of dosage of active component will be in the range of about 0.1 to about 100, more preferably about 3.0 to about 50 mg/kg of body weight/day. It is to be understood that the dosages may vary depending upon the requirements of the patient, the severity of the bacterial infection being treated, and the particular compound being used. Also, it is to be understood that the initial dosage administered may be increased beyond the above upper level in order to rapidly achieve the desired blood-level or the initial dosage may be smaller than the optimum and the daily dosage may be progressively increased during the course of treatment depending on the particular situation. If desired, the daily dose may also be divided into multiple doses for administration, e.g., two to four times per day.
The compounds of formula I according to this invention are administered parenterally, i.e., by injection, for example, by intravenous injection or by other parenteral routes of administration. Pharmaceutical compositions for parenteral administration will generally contain a pharmaceutically acceptable amount of the compound according to formula I as a soluble salt (acid addition salt or base salt) dissolved in a pharmaceutically acceptable liquid carrier such as, for example, water-for-injection and a buffer to provide a suitably buffered isotonic solution, for example, having a pH of about 3.5-6. Suitable buffering agents include, for example, trisodium orthophosphate, sodium bicarbonate, sodium citrate, N-methylglucamine, L(+)-lysine and L(+)-arginine to name but a few representative buffering agents. The compounds according to formula I generally will be dissolved in the carrier in an amount sufficient to provide a pharmaceutically acceptable injectable concentration in the range of about 1 mg/ml to about 400 mg/ml of solution. The resulting liquid pharmaceutical composition will be administered so as to obtain the above-mentioned antibacterially effective amount of dosage. The compounds of formula I according to this invention are advantageously administered orally in solid and liquid dosage forms.
The oxazolidinone antibacterial agents of this invention have useful activity against a variety of organisms. The in vitro activity of compounds of this invention can be assessed by standard testing procedures such as the determination of minimum inhibitory concentration (MIC) by agar dilution as described in xe2x80x9cApproved Standard. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobicallyxe2x80x9d, 3rd. ed., published 1993 by the National Committee for Clinical Laboratory Standards, Villanova, Pa., USA. The activity of compounds of this invention against Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pneumoniae, Enterococcus faecalis, Moraxella catarrhalis and H. influenzae is shown in Table 1.
No. 1 is Methicillin-susceptible S. aureus UC(copyright) 9213. No. 2 is Moraxella catarrhalis UC(copyright) 30610. Minimum inhibitory concentration: lowest concentration of drug (xcexcg/mL) that inhibits visible growth of the organism.